The goals of this proposal are to examine the relationship between Major Depressive Disorder (MDD) and abnormalities of the hypothalamic pituitary thyroid (HPT) axis. HPT abnormalities, specially subclinical hypothyroidism, are present in a significant number of patients with MDD. Yet the most common HPT abnormality reported in MDD is a blunted TSH response to TRH challenge suggesting central hyperactivity of the HPT axis. Perturbation of the normal functioning of the HPT axis is postulated to reflect central abnormality of TRH secretion which contribute to the heterogeneity of MDD, and plays a role in the response to antidepressant treatment. This application proposes to systematically examine the value of supplemental triiodothyronine (T3, Cytomel) with sertraline, a selective serotonin reuptake inhibitor (SSRI) in the treatment of MDD. The focus will be on two overlapping populations: 1) those with evidence of HPT abnormalities, and 2) those who did not respond to a previous adequate SSRI trial. This application proposes to programmatically develop a large study population of patients with MDD, classified with respect to HPT abnormalities and previous response to antidepressant treatment. The HPT axis will be systematically assessed in 200 patients with MDD and the benefit of triiodothyronine or placebo supplementation of sertraline examined. Half the study patients will have documented failure to a previous SSRI trial. The assessment of the HPT axis will include repeated peripheral baseline measures of TSH, total and free T3 and T4, antibodies to thyroglobulin and thyroid peroxidase; and the TRH stimulation test. Assessments will be repeated again after treatment. The primary hypothesis is that triiodothyronine supplementation sertraline will result in a greater improvement in HAM-D scores compared to placebo. Additional hypotheses will examine the role of HPT abnormalities and previous treatment response in the improvement to concomitant triiodothyronine with sertraline. This proposal is designed to provide a definitive clinical study of triiodothyronine augmentation of SSRI. It has the potential to significantly alter clinical practice in the management of MDD, particularly in patients who are non-responsive to antidepressants. The proposal will shed light on the role of the HPT axis in the pathophysiology and heterogeneity of MDD.